1. Field of the Invention
The present invention relates to the treatment of infectious diseases and, more particularly, to methods for treating infectious diseases in humans and other mammals caused by parasitic trypanosomes, bacteria, fungi and parasitic nematodes.
2. Description of the Prior Art
Infectious diseases caused by protozoa, parasitic nematodes, bacteria and fungi, are a major health issue worldwide in spite of decades of development and use of antimicrobial agents to control and treat such diseases.
Antibacterial agents have been in use since the 1940's with great success, but development of drug resistance by pathogenic bacteria has gone hand in hand with that use. Currently, multidrug resistant strains of many bacteria present a serious problem for treating infectious diseases. Thus, the need for new antibacterial drugs is great. (Payne, D. et al., Curr. Opinion. Micro., 7:435-8, 2004) In particular, gram positive bacteria such as Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pyogenes are widespread and cause a great diversity of infections and diseases in humans and animals. The diseases range from minor skin infections to life-threatening pneumonias and wound infections. (Tortora, G. J. et al., 2007. Microbiology: An Introduction, 9th ed., Pearson Benjamin Cummings, San Francisco Calif.). Drug resistant strains of S. aureus, including methicillin resistant S. aureus (MRSA) and, more recently, vancomycin resistant S. aureus (VRSA), are a major health threat. Vancomycin resistant Enterococcus (VRE) is another serious problem in human health. We are reaching a stage where there are no drugs available to treat some of these serious and life-threatening infections. (Moellering, R. C., Jr., et al., Amer. J. Medicine, 120(7):S4-S25, 2007.)
Fungal infections are perhaps even more of an issue because the number of effective antifungal drugs is limited to start with, and development of drug resistance is also an issue for these microbes. Treatment of systemic or disseminated fungal infections has a high failure rate, creating a large burden of morbidity and mortality for these infections, especially among immunocompromised individuals. Additionally, antifungal agents frequently have serious side effects that limit their usefulness and make treating of fungal infections even more challenging.
Current drug development tends to concentrate on investigating existing categories of antibacterial or antifungal agents rather than identifying novel or new types of drugs. Additionally, many pharmaceutical companies have reduced their efforts in drug development for antimicrobial agents so that there are few new drugs in the pipeline for development. (Walsh, C., Nature Reviews Microbiology 1:65-70, 2003) Natural products have traditionally been a source of new types of drugs, although that approach has lessened in recent years as the number of new drugs found from natural sources has been limited. Most antimicrobial agents derived from natural sources come from other microorganisms, although a few have been developed from nonmicrobial sources.
For hundreds and even thousands of years, medicinal plants having antimicrobial activity have been used in folklore medicine across the world, a practice generally referred to as “folk medicine” or “traditional medicine” for treating a myriad of ailments including parasitic nematode infections (Dagar, H. S. et al., Economic Botany, 45:114-119, 1991). Scientific investigations have led to the discovery of many plant-based drugs, such as quinine and artemisinin, which are well-known antimalarial derivatives from the Cinchona bark and Artemisia annua, respectively (Curtis, C. F. et al., Natural and synthetic repellants. In: Curtis C. F. (Ed.) Appropriate technology in vector control. CRC Press, 76-92, 1990; Bodeker, G. et al., Health in the Commonwealth, 9:287-289, 1998). Other plant-, D. I., Transactions of the Royal Society of Tropical Medicine and Hygiene, Supplement, 88: 17-19, 1994; Gruber, J. W. et al., Laboratory Medicine, based drugs include vinblastine, camptothecin, pancrastistatin, canasol, morphine from the opium poppy and reserpine, a hypotensive alkaloid from Indian snakeroot (Phillipson 27(2): 100-108, 1996). Drug development, however, has not kept pace with the evolution of some microorganisms and there still are no effective drugs for some types of infectious diseases.
For example, parasitic nematodes have long presented significant public health problems. There are approximately 15,000 nematodes of worldwide distribution, which parasitize both plants and animals (Croll, N. A. et al., 1977, Biology of nematodes, Blackie and Son, Glasgow). Many of these parasites are problematic because of their pathological effects on their hosts. For example, the hookworms, such as Ancylostoma duodenale and Ancylostoma caninum, are important gastrointestinal nematode parasites of humans and of both food and companion animals. These hematophagous organisms are the causative agents of severe anemia in humans, with accompanying impairment of physical growth and cognitive development (Granzer, M. et al., International Journal of Parasitology, 21(4), 429-440, 1991).
Strongyloides stercoralis, a gastrointestinal parasitic nematode of dogs, humans and other primates, was first described by Normand in 1876 and afflicts 30 to 300 million people in 70 countries. S. stercoralis infections can be exceedingly chronic and can persist in humans for thirty years or more (Grove, D. I., Strongyloidiasis, In: Warren. K. S, and Mahmoud. A. A. (Eds.), Tropical and Geographic Medicine, New York: McGraw Hill, 393-399, 1990). Although chronic infections are asymptomatic in healthy individuals, poor nutrition, ill health and/or immunosuppressive therapy can exacerbate infections, giving rise to disseminated strongyloidiasis, which can be fatal (Mansfield, L. S. et al., (1992), American Journal of Tropical Medicine and Hygiene, 47(6):830-836, 1992).
Haemonchus contortus is a highly pathogenic, economically important, gastric parasitic nematode of ruminants, including goats, sheep and cattle. This passively ingested parasite poses a worldwide threat to the goat industry, particularly in sub-temperate and temperate regions like the Southeastern United States, where infections are more prevalent. Infected goats commonly present with anemia, diarrhea, dehydration, and peripheral and internal fluid accumulation. They also have lower growth rates, markedly reduced reproductive performance and have higher rates of illness and death. Other parasitic nematodes, such as Parastrongyloides trichosuri, are considered important because they could be sources of biological control agents. P. trichosuri is a parasite-specific nematode of marsupial brushtail possums, which are a major environmental and agricultural pest in New Zealand. P. trichosuri is being evaluated as a potential self-disseminating delivery system for engineered fertility control vaccines in possums (Cowan, P. E. et al., New Zealand Journal of Zoology, 32:9-16, 2005). The pathological effects of infections by parasitic nematodes, however, far outweigh any associated potential benefits.
A variety of commercial anthelmintics has been developed to control and prevent parasitic nematode infections in humans and animals. Among these are tetramisole, levamisole, praziquantel, doramectin, the benzimidazoles, which include thiabendazole and albendazole, and ivermectin. Some of these drugs are known for their effective treatment of helminth infections. For example, ivermectin, a broad-spectrum drug, is highly effective against many parasitic nematodes including Onchocerca volvulus, H. contortus, hookworms and S. stercoralis infections in humans and animals. It also has activity against insects and acarines. Albendazole is effective against A. caninum and, along with tetramisole, has demonstrated 100% efficacy rates against H. contortus infections. Doramectin was shown to reduce P. trichosuri infections in possums by 99%.
However, while some anthelmintics are remarkable in their treatment, others have demonstrated poor efficacy. For example, thiabendazole has been the drug of choice for treating strongyloidiasis, but its relative high cost, poor efficacy and associated unpleasant side effects have militated against its use, particularly in third world countries of the tropics where infections are most prevalent. Along with the rise of drug resistance by parasitic nematodes, the search for alternative sources of treatment is an urgent on-going process. For example, high-level anthelmintic resistance has been demonstrated by A. caninum against pyrantel (Kopp, S. R. et al., Veterinary Parasitology, 143(3-4): 299-304, 2007), and H. contortus has exhibited resistance against the benzimidazoles (Tiwari, J. et al., Veterinary Parasitology, 138(3-4): 301-307, 2006) and ivermectin (Gill, J. H. et al., International Journal of Parasitology, 21(7), 771-776, 1991; Vickers, M. et al., New Zealand Veterinary Journal, 49(3):101-105(5), 2001).
In Jamaican Letters Patent 3325, entitled “Medicaments for the treatment of Strongyloides stercoralis infections [anthelmintic activity of E-2-dodecenal, derived from Eryngium foetidum (Ammiaceae), against Strongyloides stercoralis (Nematoda)],” issued Sep. 23, 2002, there is disclosed anthelmintic activity of trans-2-dodecenal derived from Eryngium foetidum against the parasitic nematode Strongyloides stercoralis. This patent discloses an in vitro study of trans-2-dodecenal (eryngial) taken for various durations of time, but does not disclose dose-response parameters for eryngial against S. stercoralis. 
Another example of a class of parasitic microorganisms is parasitic trypanosomes. Currently, there are very few active agents to treat diseases caused by these microorganisms. The drugs that are available are expensive and often have associated side effects that militate against their use by infected individuals. More worrisome is the increase in the number of drug-resistant trypanosomes (Kaminsky, R. et al., Acta Tropica, 54:279-289, 1993.).
In the past, plant compounds have been shown to be somewhat successful in displaying anti-trypanosomal properties. For example, muzigadial, derived from a Ugandan medicinal plant (Warburgia ugandensis), has shown trypanocidal characteristics similar to diminazene aceturate and geneticin. Both are popular anti-trypanosomal agents (Ma, D. et al., African Journal of Biotechnology, 4: 134-137, 2005).
It is difficult, however, to find compounds that are effective against trypanosomes because they have a variant-specific glycoprotein (VSG) coat. Effective treatment further is complicated by the trypanosome's ability to switch from one VSG to another (Rifkin, M. R., National Academy of Sciences, 87:801-805, 1990).
Trypanosomes are flagellated protozoa of the genus Trypanosoma. Various species of Trypanosoma cause numerous diseases in humans and other mammals. For example, Trypanosoma brucei gambiense and Trypanosoma brucie rhodesiense cause trypanosomiasis, also referred to as African sleeping sickness, transmitted by tsetse flies of the genus Glossina. 
In South America, a different trypanosome, Trypanosoma cruzi, causes Chagas disease, which affects the nervous system and heart. This parasite is not transmitted by tsetse flies but by a different type of blood-sucking arthropod, Triatoma infestans, also referred to as the triatomine kissing bug. (Schmidt, G. D. and Roberts, L. S., 1989, Foundations of Parasitology, 4th ed. St. Louis: Times Mirror/Mosby, p. 55-79). Other species, restricted in distribution to Africa and Asia, cause diseases of horses and cattle. Control measures include elimination or reduction of the insect carrier populations and measures to reduce the likelihood of bites.
Trypanosomes have a complex life cycle. They use invertebrate hosts, such as insects and leeches, which then transmit the parasite to vertebrate animals. Domesticated animals, such as dogs, cats and cattle, can serve as reservoir hosts for these parasites before they are passed to humans (Abenda, J. N., African J. Biotechnology, 4: 134-137, 2005). For example, T. cruzi exists as a long, slender trypomastigote form that circulates in a vertebrate animal's blood. Trypomastigotes are ingested by an insect vector (triatomine bugs) during a blood meal. The parasites migrate to the insect's midgut where they change to an epimastigote form, which subsequently multiplies to become metacyclic trypanosomes. These forms are short and stumpy and are passed via feces from the insect vector and deposited on the skin of an unsuspecting vertebrate. They enter the vertebrate through mucus membranes or scratched skin and travel in the blood to muscle tissue. In the muscle tissue, they lose their flagella, change to an amastigote form, reproduce and then change to a trypomastigote form. These then enter and circulate in the vertebrate's blood stream where they can be ingested by an insect during a blood meal. (Schmidt, G. D. and Roberts, L. S., 1989, Foundations of Parasitology, 4th ed., St. Louis: Times Mirror/Mosby, p. 55-79).
There is a need, therefore, for new types of antimicrobial drugs to treat infections caused by parasitic protozoa, bacteria, fungi and nematodes.